The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRs
Positive allosteric modulators for free fatty acid receptor 2 (FFAR2/GPR43), that affect receptor function through binding to two distinct allosteric binding sites, were used to determine the correlation between the responses induced in neutrophils by two distinct activation modes; FFAR2 was activat...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079109/?tool=EBI |
| _version_ | 1797850342028738560 |
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| author | Simon Lind Kenneth L. Granberg Huamei Forsman Claes Dahlgren |
| author_facet | Simon Lind Kenneth L. Granberg Huamei Forsman Claes Dahlgren |
| author_sort | Simon Lind |
| collection | DOAJ |
| description | Positive allosteric modulators for free fatty acid receptor 2 (FFAR2/GPR43), that affect receptor function through binding to two distinct allosteric binding sites, were used to determine the correlation between the responses induced in neutrophils by two distinct activation modes; FFAR2 was activated either by the orthosteric agonist propionate or by a receptor transactivation mechanism that activated FFAR2 from the cytosolic side of the neutrophil plasma membrane by signals generated by the neutrophil PAFR (receptor for platelet activating factor), P2Y2R (receptor for ATP), FPR1 (receptor for fMLF) and FPR2 (receptor for WKYMVM). We show that the transactivation signals that activate FFAR2 in the absence of any orthosteric agonist were generated downstream of the signaling G protein that couple to PAFR and P2Y2R. This transactivation of allosterically modulated FFAR2s, by signals generated by PAFR/P2Y2R, represents a novel mechanism by which a G protein coupled receptor can be activated. Weak correlations were obtained when the FFAR2 activity was induced by the transactivation signals generated by PAFRs and P2Y2Rs were compared with the FFAR2 activity induced by the orthosteric agonist propionate. Comparison of the responses for each allosteric modulator revealed that the ratio values, calculated from the peak values of the ATP and propionate responses, varied from 0.2 to 1. Depending on the allosteric modulator, the response induced by the two different mechanisms (orthosteric activation and receptor transactivation, respectively), was equal or the propionate response was more pronounced. Importantly, we conclude that FFAR2 activation from outside (orthosteric activation) and inside (receptor cross-talk/transactivation) can be selectively affected by an allosteric FFAR2 modulator. |
| first_indexed | 2024-04-09T18:58:50Z |
| format | Article |
| id | doaj.art-fb9cc0e369744816aac669113d5dc39e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-09T18:58:50Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-fb9cc0e369744816aac669113d5dc39e2023-04-09T05:32:15ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01184The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRsSimon LindKenneth L. GranbergHuamei ForsmanClaes DahlgrenPositive allosteric modulators for free fatty acid receptor 2 (FFAR2/GPR43), that affect receptor function through binding to two distinct allosteric binding sites, were used to determine the correlation between the responses induced in neutrophils by two distinct activation modes; FFAR2 was activated either by the orthosteric agonist propionate or by a receptor transactivation mechanism that activated FFAR2 from the cytosolic side of the neutrophil plasma membrane by signals generated by the neutrophil PAFR (receptor for platelet activating factor), P2Y2R (receptor for ATP), FPR1 (receptor for fMLF) and FPR2 (receptor for WKYMVM). We show that the transactivation signals that activate FFAR2 in the absence of any orthosteric agonist were generated downstream of the signaling G protein that couple to PAFR and P2Y2R. This transactivation of allosterically modulated FFAR2s, by signals generated by PAFR/P2Y2R, represents a novel mechanism by which a G protein coupled receptor can be activated. Weak correlations were obtained when the FFAR2 activity was induced by the transactivation signals generated by PAFRs and P2Y2Rs were compared with the FFAR2 activity induced by the orthosteric agonist propionate. Comparison of the responses for each allosteric modulator revealed that the ratio values, calculated from the peak values of the ATP and propionate responses, varied from 0.2 to 1. Depending on the allosteric modulator, the response induced by the two different mechanisms (orthosteric activation and receptor transactivation, respectively), was equal or the propionate response was more pronounced. Importantly, we conclude that FFAR2 activation from outside (orthosteric activation) and inside (receptor cross-talk/transactivation) can be selectively affected by an allosteric FFAR2 modulator.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079109/?tool=EBI |
| spellingShingle | Simon Lind Kenneth L. Granberg Huamei Forsman Claes Dahlgren The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRs PLoS ONE |
| title | The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRs |
| title_full | The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRs |
| title_fullStr | The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRs |
| title_full_unstemmed | The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRs |
| title_short | The allosterically modulated FFAR2 is transactivated by signals generated by other neutrophil GPCRs |
| title_sort | allosterically modulated ffar2 is transactivated by signals generated by other neutrophil gpcrs |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10079109/?tool=EBI |
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